New Findings What is the topic for this review?We discuss the dichotomization of continuous‐level physiological measurements into ‘responders’ and ‘non‐responders’ when interventions/treatments are examined in robust parallel‐group studies. What advances does it highlight?Sample responder counts are biased by pre‐to‐post within‐subject variability. Sample differences in counts may be explained wholly by differences in mean response, even without individual response heterogeneity and even if test–retest measurement error informs the choice of response threshold. A less biased and more informative approach uses the SD of individual responses to estimate the chance a new person from the population of interest will be a responder. Abstract As a follow‐up to our 2015 review, we cover more issues on the topic of ‘response heterogeneity’, which we define as clinically important individual differences in the physiological responses to the same treatment/intervention that cannot be attributed to random within‐subject variability. We highlight various pitfalls with the common practice of counting the number of ‘responders’, ‘non‐responders’ and ‘adverse responders’ in samples that have been given certain treatments or interventions for research purposes. We focus on the classical parallel‐group randomized controlled trial and assume typical good practice in trial design. We show that sample responder counts are biased because individuals differ in terms of pre‐to‐post within‐subject random variability in the study outcome(s) and not necessarily treatment response. Ironically, sample differences in responder counts may be explained wholly by sample differences in mean response, even if there is no response heterogeneity at all. Sample comparisons of responder counts also have relatively low statistical precision. These problems do not depend on how the response threshold has been selected, e.g. on the basis of a measurement error statistic, and are not rectified fully by the use of confidence intervals for individual responses in the sample. The dichotomization of individual responses in a research sample is fraught with pitfalls. Less biased approaches for estimating the proportion of responders in a population of interest are now available. Importantly, these approaches are based on the SD for true individual responses, directly incorporating information from the control group.

It has recently been reported how to quantify inter-individual differences in the response to an exercise intervention using the standard deviation of the change scores, as well as how to appraise these differences for clinical relevance. In a parallel-group randomised controlled trial, the key trigger for further investigation into inter-individual responses is when the standard deviation of change in the intervention sample is substantially larger than the same standard deviation derived from a suitable comparator sample. 'True' and clinically relevant inter-individual differences in response can then be plausibly expected, and potential moderators and mediators of the inter-individual differences can be explored. We now aim to critically review the research on the inter-individual differences in response to exercise training, focusing on maximal oxygen uptake (VOmax). A literature search through the relevant bibliographic databases resulted in the identification of six relevant studies that were published prior to the influential HEalth, RIsk factors, exercise Training And GEnetics (HERITAGE) Family Study. Only one of these studies was found to include a comparator arm. Re-analysis of the data from this study, accounting for random within-subjects variation, revealed an absence of clinically important inter-individual differences in the response of VOmax to exercise training. The standard deviation of change was, in fact, larger (±5.6 mL/kg/min) for the comparator than the intervention group (±3.7 mL/kg/min). We located over 180 publications that resulted from the HERITAGE Family Study, but we could not find a comparator arm in any of these studies. Some authors did not explain this absence, while others reasoned that only inter-individual differences in exercise response were of interest, thus the intervention sample was investigated solely. We also found this absence of a comparator sample in on-going studies. A perceived high test-retest reliability is offered as a justification for the absence of a comparator arm, but the test-retest reliability analysis for the HERITAGE Family Study was over a much shorter term than the length of the actual training period between baseline and follow-up measurements of VOmax. We also scrutinised the studies in which twins have been investigated, resulting in concerns about how genetic influences on the magnitude of general within-subjects variability has been partitioned out (again in the absence of a comparator no-training group), as well as with the intra-class correlation coefficient approach to data analysis. Twin pairs were found to be sometimes heterogeneous for the obviously influential factors of sex, age and fitness, thereby inflating an unadjusted coefficient. We conclude that most studies on inter-individual differences in VOmax response to exercise training have no comparator sample. Therefore, true inter-individual differences in response cannot be quantified, let alone appraised for clinical relevance. For those studies with a comparator sample, we found tha...

Previous reports of substantial inter-individual differences in weight change following an exercise intervention are often based solely on the observed responses in the intervention group. Therefore, we aimed to quantify the magnitude of inter-individual differences in exercise-mediated weight change. We synthesized randomized controlled trials (RCTs) of structured, supervised exercise interventions. Fourteen electronic databases were searched for relevant studies published up to March 2017. Search terms focused on structured training, RCTs and body weight. We then sifted these results for those RCTs (n = 12, 1500 participants) that included relevant comparator group data. Standard deviations (SDs) of weight change were extracted, thereby allowing the SD for true inter-individual differences in weight loss to be calculated for each study. Using a random effects meta-analysis, the pooled SD (95% CI) for true individual responses was 0.8 (-0.9 to 1.4) kg. The 95% prediction interval (based on 2SDs) for true inter-individual responses was -2.8 to 3.6 kg. The probability (% chance) that the true individual response variability would be clinically meaningful (>2.5 kg) in a future study in similar settings was 23% ('unlikely'). Therefore, we conclude that evidence is limited for the notion that there are clinically important individual differences in exercise-mediated weight change.

We recently reported how to quantify the inter-individual differences in response to an intervention. We now aim to scrutinise the research on the individual responses to training of maximal oxygen uptake (VO2max). The key trigger for further investigation into individual responses is when the standard deviation of change (SDchange) in the intervention sample is substantially larger than the same standard deviation derived from a suitable comparator sample. ‘True’ inter-individual response can then be inferred. Six relevant studies from the influential HERITAGE family study were published in the 1980s. Unfortunately, only one of these studies included a comparator arm (1) Re-analysis of data from this study, accounting for random within-subjects variation, revealed an absence of clinically important individual difference in VO2max response. The SDchange was, in fact, larger (±5.6 ml/kg/min) for the comparator than the intervention group (±3.7 ml/kg/min). Over 180 publications have now resulted from The HERITAGE study, but the crucial comparator arm is absent in all of these studies. Some authors rationalized this absence by claiming that only inter-individual differences in exercise response were of interest. This absence of a comparator sample is also the case in some present on-going studies. Again, re-analysis of data from the most recent studies does not suggest clinically relevant inter-individual differences in response. We also have concerns about the intraclass correlation coefficient approach to data analysis in twin studies. These are often heterogeneous for the obviously influential factors of sex, age and fitness, thereby inflating an unadjusted coefficient. We conclude that most studies on individual differences in VO2max response have no comparator sample. Therefore, ‘true’ individual response differences cannot be quantified. For those studies with a comparator sample, the difference between individual differences in response and random within-subjects variation is not clinically relevant.

No abstract